Quaternary ammonium compounds



Patented Aug. 28,- 1951 UNITED STATES FA-TENT OFFICE ouArsaNAav AMMONIUM COMPOUNDS;

of Illinois No Drawing. Application January 9, 1947, Serial No. 721,153

12 Claims.

This invention concerns three new classes of quaternary ammonium compounds having antiseptic properties such that germicidal action is obtainable in very dilute solutions, while at the same time additional dilution can be practiced while still retaining bacteriostatic action. These compounds are derivatives of heterocyclic nitrogen parent compounds, with an alkyl group bonded to the quaternary nitrogen, which alkyl is of the higher alkyl, or long, type, in the sense that it contains not less than ten carbon atoms. The parent compounds are: (l) negatively substituted 3-pyridines, (2) tetrahydroquinolines and (3) tetrahydroisoquinolines.

The term antiseptic as used in this specification refers to a substance which prevents or arrests the growth of microorganisms either by in- 2 and sulfamyl (SONH2) did not enhance the properties of this type of antiseptic. In fact, and it is rather surprising, the carboxyl group in the 3-position of the pyridinium molecule almost completely destroys the germicidal activity and the sulfamyl radical greatly decreases the activity.

The designation, negative groups, is here used to refer to those groups of atoms which when attached to an organic compound make that compound more negative, 1. e. more acidic. Included inthis classification are the above mentioned groups and others such as sulfonic, nitro, nitrosyl, etc.

The lowering of the toxicit brought about by the introduction of a halogen atom into the 3- position of the pyridinium nucleus is illustrated by the following comparison:

Compound Toxicity: Mice: MgJKg.

Name Structure 331E535 i t g gsl Oral Br CmHas 60 400 3-Bromo-N-cety1pyridinium halide N 0151333 8 8 N-Cetylpyridinium halide N:

hibiting their activity or destroying them. The word germicide refers to an agent which destroys microorganisms.

GROUP 1 The first group of compounds is the quaternary ammonium derivatives of negatively substituted S-pyridines which have the general structure:

The definition of toxicity as used here refers to the amount that will kill of the animals tested. This toxicity is commonly expressed as L. D. 50.

To illustrate the effectiveness of these negatively substituted pyridinium antiseptics, data on 3- bromo-N-tetradecy1pyridinium chloride are given below: 0

Concentration Compound Bactcriostatic Germicidal, 45 51nin..

S. aurcus S. aureus S. fecalzs -Br 50, 000 1, 000, 000 500, 000 .0 l

55 The figures given are the highest dilution for other negative groups as the carboxyl (--COOH) killing the germs in five minutes, and the highest dilution for inhibiting germ growth according to the Food and Drug Administration method.

The compounds of this group may be prepared b allowing the desired 3-substituted pyridine to react with the appropriate alkyl halide. Generally, a solvent is not needed but one such as alcohol, benzene, toluene, carbitol and the like may be used in some instances. It is advantageous to have a slight excess of alkyl halide. The temperature required to effect reaction depends largely on the halogen employed in the X position and to a lesser extent on the nature of the group in the 3-position (as Y). In general, it may be stated that for alkyl chlorides temperatures are required somewhat over 150 C. to effect condensation; alkyl bromides react well at about 130 C. (or lower if longer reaction times are employed); while alkyl iodides condense readily at about 100 C.

Given below are some of the compounds prepared from the 3-substituted pyridines.

it Y

EXAMPLE 3 3-chloro-N-tetradecylpyridinium bromide.-A mixture of 22.7 grams of 3-chloropyridine and about 65 grams of tetradecyl bromide is heated for 1820 hours at about 115-120 C. At the end of this time, the reaction mixture solidifies on cooling. It is stirred thoroughly with petroleum ether and the solid separated by filtration and washed well with petroleum ether. The crude material thus obtained may be purified by recrystallization from ethyl acetate, yielding glistening plates melting at 7l-'72.

GROUP 2 The second group of compounds is the quaternary ammonium derivtives of tetrahydroquinolines. These new compounds have a partiall reduced quinoline nucleus. Compounds coming 3-(Y) Substituted Pyridium Alkyl Halides Substituents M. P., C.

Y R (normal) X O H2 Decyl 75 76. C11H2a, Undecyl. O11.

C15H3:l, can. 98-100; 85; 81-82.

C sH37, Octadecyl l05.5l06.5. -C1sl135, 9-Octadeccnyl 82-83. (CH2)2"'O(CHZ)ZOC6H4CH3*P, p-Toloxyethoxyethyl. 73-74.

C1 C14H2g, Tetradecyl 71-72.

. Examples are given below of the preparation of three of the above compounds:

3-halogen0-N-alkylpyridinium halides EXAMPLE 1 3-bromo-N-tetmdecylpyridinium chZ0rz'de..A mixture of 16 grams of 3-brornopyridine and about grams of tetradecyl chloride is heated for about 20 hours at approximately l-160 C.

At the end of this time, the reaction mixture is allowed to cool and is then poured into petroleum ether. The gray crystalline solid is separated from the mixture by filtration, and washed well with petroleum ether. The crude product thus obtained may be purified by recrystallization from ethyl acetate, yielding fine, colorless needles melting at about 90--91 C.

EXAMPLE 2 3 bromo N 9 octadecenylpyridinium bromide-Reaction is elfected between 16 grams of 3-bromopyridine and about l0 grams of 9-octadecenyl bromide by heating this mixture for about 20 hours at somewhat over 100 C. The reaction mixture is then cooled and stirred thoroughly with pcntane. The somewhat mushy, soapy solid is separated from the liquid phase by centrifugation and washed several times with pentane by the same process. Finally, after separating the crude material and drying in a vacuum desiccator, it is recrystallized from ethyl acetate containing a few percent of methyl alcohol.

-3-bromo-N-octadecenylpyridinium bromide crystallizes in colorless clusters melting at 82-83" C.

within the scope of this invention may be represented by the following general formula:

decyl-l, 2, 3, atetrahydroquinolinium chloride gives the following results:

- Bacteriostatic Germicidal Toxicity Com ound Concentrw Concentration mgi/kgl" p tion,5min., Oral; amen? S. aurcus S. fccalis Mme CH; 01 CuHzv l Two syntheses are available for the preparation of these compounds: Process A and Process B. Of the two, Process B is the preferred since it gives excellent yields and is more satisfactory in general.

Process A CHQX RX (NaOH) i i i H OH; R X CH:

Tetrahydroqulnoline N-methyltetrahydrcquinolinc PTOCCSS B 2H1 CHSX (Ni) (NaOH) l R X B. R X OH: Long chain alkyl N-R-tetrahydroquinolinium halide quinohne Given below are some of the compounds which have been prepared by Process B:

N-alkyl-N-methi l-1,z,8,4-tztrahydroguinolinium halides The conversion of the quaternary ammonium iodides to the corresponding bromides or chlorides is described in the specific examples belows:

EXAMPLE 4 N-methyl-N-tetradecyl-l, 2, 3, 4-tetrahydroquinolinium iodide.-A solution of 32.9 grams of N-tetradecyltetrahydroquinoline (for the preparation of this compound see co-pending application, Serial Number 721,154, filed January 9, 1947, now Patent 2,524,392) and about 16 grams (slight excess) of methyl iodide in '75 cc. of dry benzene is refluxed on the steam bath for approximately 20 hours. Atthe end of this time, the benzene is removed by warming the reaction mixture under vacuum and the residue remaining is treated with an excess of petroleum ether. The crude solid is separated by filtration and purified by recrystallization from ethyl acetate, forming fine light yellow crystals melting at 7576 C.

- decyl-G -hydroxy-N-methylquinolinium Instead of preparing N-tetradecyltetrahydroquinoline by the method referred to above, one may prepare it by heating 66.0 grams of tetrahydroquinoline and about 140 grams of tetradecyl bromide in 200 cc. of dry benzene at refluxing temperature for 18 hours. After removing the solvent at the end of this time by distillation in vacuo, the residue is made alkaline with. excess 10% sodium hydroxide solution and the oily product extracted with benzene. The benzene layer is separated, dried and concentrated in the absenceof air under vacuum. Then the residue is distilled under diminished pressure and the N-tetradecyl-l, 2, 3, 4-tetrahydroquinoline is collected at about 205 at 4 mm.

The latter procedure is less satisfactory than the former, particularly with respect to yield.

EXAMPLE 5 N-methyZ-N-tetradecyl-l, 2, 3, 4-tetrahydroquinolinium chloride.About 10 grams of N- methyl N tetradecyltetrahydroquinolinium iodide is treated with an excess of freshly precip itated silver chloride by refluxing in 200 cc. of of alcohol ford-8 hours. At the end of this time the precipitated silver iodide plus excess silver chloride is separated by filtration and the filtrate evaporated to dryness under vacuum on the water bath. The oily residue is then taken up in the smallest amount of water to afford complete solution, frozen and lyophilized from the solid state. The material is a clear, sticky mass at room temperature and fails to crystallize on standing.

By using silver bromide instead of silver chloride, the iodide may be converted to N-methyl- N-tetradecyltetrahydroquinolinium bromide by the same procedure.

EXAMPLE 6 N hemadecyl-fi-hydroxy- N methyZ-1,2,3,4-tetrahydroquinolinium; iodide.--A dry benzene cc.) solution of 3.5 grams of N-hexadecyl-S-hydroxy-quinoline (for the preparation of this compound see co-pending application, Serial Number 721,154, filed January 9, 1947, now Patent 2,524,392) and about 2.0 grams of methyl iodide is refluxed on the steam bath for 20 hours. At the end of the first 10 hours of this refluxing period, a further 1 gram quantity of methyl iodide is added to replace any that may have been lost through volatilization. The solvent is then removed by heating under vacuum and the residue washed well with petroleum ether by decantation. The crude product remaining is dissolved in hot ethyl acetate plus a trace of methanol and cooled. On standing, colorless crystals of the iodide separate, melting about 117 C. Repeated crystallization of this material from this solvent does not raise the melting point above 1l'7-118 C.

This iodide salt maybe converted to the corresponding chloride by the silver chloride procedure given in theabove Example 5. N-hexachloride is a colorless solid melting at about 134-135 C.

GROUP 3 The third group of quaternary ammonium compounds to be considered in this invention are the quaternary ammonium derivatives of the tetrahydroisoquinolines. These compounds are derivatives of a partially reduced isoquinoline nucleus having a higher alkyl group attached to the quaternary ammonium nitrogen atom. These fsilver chloride in water. as a solvent in place of water, in which case the 7 compounds may be represented by the following general formula:

t R H I wherein R is a monovalent higher alkyl group containing at least ten carbon atoms; R is a. low molecular weight alkyl group; Y is a monovalent group such as hydrogen, alkyl, hydroxyl, etc.;

X is an anion.

These compounds may be prepared by the same After removal of the silver halide by filtration,

Below are several specific examples of th preparation of these compounds:

EXAMPLE 7 N methyl N tetradecyZ-I ,2,3,4-tetrahydroisoquinolz'nium iodide.--Asolution of 16.4 grams of N-tetradecyl-12,3,4-tetrahydroisoquinoline (for the'preparation of this compound see co-pending application, Serial Number 721,154, filed January 9, 1947, n0w Patent 2,524,392) and about 8 grams of :methyl iodide in 100 cc. of dry benzene is refluxed on the'steam bath for approximately imay lee-purified by recrystallization from ethyl acetate giving pale yellow crystals melting at 92-93 C.

Conversion of the iodide to N methyl N tetradecyl 1,2,3,4 tetrahydroisoquinolinium chloride, can be accomplished by shaking overnight 5.0 grams of the former with an excess of Alcohol may be used mixture is refluxed instead of being shaken.

. EXAMPLE 8 processes as given for the tetrahydroqulnolmium 1o compounds above. These compounds are very N m thyl methyl N dodecyl 1,2,3,4 effective germicides and Show fairly 1 toxicity tetmhydrozsoqumolzmum wdzde.A solution. of to warm-blooded animals. Given below are some 22 grams y y rlBfiA-t w of the compounds which have been prepared from hydrolsoqllmolme (for the preparatlon, ee 00- these methods and a few of their antiseptic 2O p d g pp Serial Number ,-fi d pro'pertiesz January 9, 1947, now Patent 2,524,392) and about 10 grams of methyl iodide in 100 cc. of ethyl i 1: I 1 h ld N,N dmlkyl1,2,5,t etra LII/(ZZZSOQMMLOZMHIHH at es a cohol is refluxed for 14 hours" At the end-of this time, thesolvent is removed by vacuum dis- R tillation and the residue allowed to s'tand'for 24 hours at room temperature. It is then dissolved in 100 cc. of ethyl acetate and cooled for several hours. The solid product 'Substituents Concentration P" Germk Bacteriostatic' C cidal, R (Normal) R X 5 min 1 S. mucus S. aurcus S. jecalis IC10Hn CH3...

"C13H25 CH3...

P0141129 CH3...

" C16H33 CH3. B

4118113, oh3 .l C l]129 C2115" (CH2)r-O(CH2)2O-CsH5CHa-p CH3.-- 1 2H2: Y=3CH3 CH3...

which separates is removed by filtration and dried in a vacuum drying oven at C. This crude material may be purified by recrystallization from light yellow crystals melting at -101 C.

EXAMPLE 9 N ethyl N tetmdecyl 1,2,3,4 tetrahydroisoquinolz'm'um iodide-A solution of 16.4 grams N tetradecyl 1,2,3/i tetrahydroisoquinoline PREPARATIONS Compounds according to the invention may be made up into a variety of pharmaceutical vehicles for the application of thes antiseptic compounds. Among the types of compositions of matter which have been prepared and used successfully are aqueous solutions, tinctures, dusting powders, etc. r

Due to the highly germicidal propertiesv and low toxicities of the quaternary ammonium-compounds described, these preparations have many and-varied applications in preventing and curingprepared inany desirable amount bydissolving 1 unit by weight of the quaternary ammonium compound in 1009 units of distilled water.

A suitable tincture'using S bromo N tetra decylpyridinium chloride may be made up as fol- IOWSI EXAMPLE A composition in the following concentrations: For 100 cc. volume- 0.1 gm. 3-brom0 N-tetradecylpyridinium chloride 54.0 cc. ethyl alcohol denatured 5.0 cc. acetone Q. S. distilled water EXAMPLE 1 l The antiseptic compounds herein disclosed may be made up for use in powder form in conventional ways such as embodying about 1% of the active ingredient in a therapeutically inert vehicle. One suitable vehicle is carboxymethylcellulose and a convenient way for incorporating these materials in such a vehicle is to make up an acetone and water solution to be mixed with the vehicle, after which the combined mass is dried in conventional ways.

All of the alkyl groups mentioned in the foregoing description are straight chain, or normal, alkyl groups.

Others may readily adapt th invention for use under various conditions of service, by employing one or more of the novel features disclosed, or equivalents thereof. As at present advised with respect to the apparent scope of our inventions, we desire to claim the following subject matter.

We claim:

1. An antiseptic composition of matter consisting of a solution containing as the active ingredient a compound consisting of a 1,2,3,4-tetrahydroquinoline nucleus; the nitrogen in said nucleus carrying as substituents a lower alkyl group, a higher alkyl group of more than 9 and less than 19 carbon atoms, and an anion.

2. An antiseptic composition of matter consisting of a solution containing as the active ingredient a compound consisting of a 1,2,33,4- tetrahydroisoquinoline nucleus; the nitrogen in said nucleus carrying substituents including an alkyl group of more than nine and less than nineteen carbon atoms, and an anion; said nitrogen having no hydrogen bonded to it.

3. Tetrahydroquinoline derivatives of the following type:

wherein R' is an alkyl group containing more than nine and less than nineteen carbon atoms; R is a low molecular weight alkyl group; Y is a monovalent group selected from a class consist- 10 ing of hydrogen, hydroxyl, methoxyl and halogen: X is an anion.

4. Tetrahydroisoquinoline derivatives of the following type;

bi -R ti X wherein R is an alkyl group containing more than nine and less than nineteen carbon atoms; R. is a low molecular weight alkyl group; Y is a monovalent group selected from a class consistr ing of hydrogen, hydroxyl, methyl, and halogen;

Xis an anion.

5. N-methyl-N-tetradecyl-1,2,3,4 tetrahydroquinolinium chloride represented by the following formula:

N C1 CuH29 6. N-methyl-N hexadecyl-1,2,3,4-tetrahydro quinolinium iodide represented by the following formula:

N i CH3 I CmHss '7. G-hydroxy-N methyl-N-hexadecyl 1,23,4-

tetrahydroquinolinium iodide represented by the following formula:

N of, I o,.n2g

8. N-methyl-N-tetradecyl 1,2,3,4-tetrahydroisoquinolinium chloride represented by the following formula:

10. A compound selected from the group consisting of l,2,3,4-tetrahydroquinoline and 1,2,31,4- tetrahydroisoquinoline, the nitrogen in the quinoline heterocyclic nucleus carrying as a substituent an anion and as additional substituents a N -lower alkyl group and a N -higher alkyl group, said higher alkyl group containing 10-18 carbon atoms.

11. A 1, 2, 3, 4-tetrahydroquinolinium halide, characterized by the presence of a Iii-methyl group and as an additional substituent a N- higher alkyl group having ten to eighteen carbon atoms inclusive.

12. A 1,2,3,4-tetrahydroisoquinolinium halide, characterized by the presence of a NT-methyl er alkyl group having ten to eighteeh ca'i'kien" atoms -inciusive'; h V V MARLIN T. LEFFLER; WAVERLY' D. KRUEGER.

mm'eer Name- Date 2,104,723 Ber'ts'ch'et a1 Jeri. 11, 1938 2,194,399 Lange Maf.19,'194'0' 2,264,150 Hlitei et 'al NOV. 25, 1941 2,295,504 Shelton Sept 8,1942 2,295,505 sheltbn Se t; 8, 1942 2,386,936 DeGi'Odt efi'aJ 0017.16; 1945' OTHER REFERENCES 10 Sidgwick: Organic Chemistry- 0f (OxiordUniv. Press, 1937), pages 563 12111} 564:

' 757-759 (Ma 194 v Hoogerbeide: J. of Bacteriology, March 1915; 

1. AN ANTISEPTIC COMPOSITION OF MATTER CONSISTING OF A SOLUTION CONTAINING AS THE ACTIVE INGREDIENT A COMPOUND CONSISTING OF A 1,23,4-TETRAHYDROQUINOLINE NUCLEUS; THE NITROGEN IN SAID NUCLEUS CARRYING AS SUBSTITUTENTS A LOWER ALKYL GROUP, A HIGHER ALKYL GROUP OF MORE THAN 9 AND LESS THAN 19 CARBON ATOM, AND AN ANION. 